Methods of preparing alpha-amino acids and n-substituted-alpha-amino acids



Patented Jan. 6, 1948 ,UNlTED STATES PATENT OFFICE" METHODS OF PREPARINGa-AMINO ACIDS AND N-SUBSTITUTED-a-AMINO ACIDS John H. Billman,Bloomington, Ind.

No Drawing. Application October 5, 1945 16 Claims. (01. 260-531) Thisinvention relates to methods of preparing a-amino acids andN-substituted-u-amino acids.

The present application is a'continuatlon in part of my copendingapplication Serial No. 411,555, filed September 19, 1941, now Patent No.2,394,230, granted February 5, 1946.

Amino acids have long been recognized as essential to biologicalprocesses in most living' things and more recently have been utilized tosustain life. Numerous 'methods have heretofore been employed for thesynthesis of these amino acids and more particularly the a-amino acids.-

For example, some of these methods have been used which involve theamination of a-halogenated acids, the Gabriel synthesis, and theStrecker synthesis. All of these methods, however, have the commondisadvantage of being rather lengthy, expensive, and usually yieldingsmall amounts of amino acids.

In accordance with this invention, u-amino acids andN-substituted-m-amino acids are prepared by a method which isefflcientand economical. This method comprises protecting the aminogroup of a fi-amlno alcohol containing no aliphatic unsaturated group,oxidizing the protected p-amino alcohol to the corresponding a-aminoacid by converting its methylol group into a carboxyl group, and thenremoving the protecting group; This protection is achieved by reactingthe fi-amino alcohol with an aldehyde, either aromatic or aliphatic;which aldehyde contains a divalent group which attaches itself to andprotects by rendering unoxidizable the aminoradical of the fl-aininoalcohol during the subsequent oxidation of the methylol group of thealcohol to the carboxyl group. That divalent group which protects theamino radical during oxidation of the c-amino alcohol and which isderived from the aldehyde is:

I at:

in which R is an alkyl radical or an aryl radical containing nounsaturated aliphatic substituent and containing no non-hydrocarbonoxidizable substituent. Examples of the radical R are the monovalentradicals derived from ethane, propane, chloroethane, benzene,chlorotoluene, nitrobenzene, chlorobenzene, naphthalene, benzoic 2 acid,benzene sulfonlc acid, diphenyl, anisol ethyl benzoate, and ethyl ether.

The reaction which takes place in protecting the ,B-amino alcohol byreaction with an aldehyde is represented bythe following equation:

I R, v H R1 R-C=0 Nm-( al-ongon -l n-tm-d in-omon mo i which each of R1and R4 is hydrogen, an alkyl radical, or an aryl radical containing nounsaturated aliphatic group.

The resulting protected p-amino alcohol is then oxidized to thecorresponding u-amino acid, by converting. the methylol group of thealcohol to a carboxyl group. This oxidation may'be performed by anysuitable oxidizing agent, such as: a metallic permanganate, for examplean alkali- I metal permanganate, an alkaline-earth metaloxidation-reduction potentials.

permanganate, or zinc permanganate, in an aqueous medium of anyreaction, whether alkaline, acid, or neutral; a chromic oxidizing agent,in-. cluding chromic acid CrOa, metallic dichromates, and metallicchromates, such as sodium dichro-' mate, in an acid medium; an oxidizingacid, including, in addition to the chromic acid already named,persulfuric acid, chloric acid, or nitric acid; lead peroxide; or ferricchloride; all of Sometimes the resulting product, instead of beinganacid as indicated by Equation 3, might be a salt of the acid, such asthe sodium salt. A salt -is formed if the oxidation is performed in abasic medium, such as in the presence of sodium hydroxide or sodiumcarbonate.

After the protected p-amino alcohol has thus ethylidene group,

been oxidized to the corresponding u-amino acid, the resulting compoundis decomposed (hydrolyzed) to form an e-amino acid. This decomposition(or hydrolysis) may, plished by hydroiyzing the resulting oxidationcompound with a mineral acid, such as hydrochloride or sulfuric acid, ora base, such as sodium or barium hydroxide.

The overall reaction which takes place is represented as follows:

( E R1 R,

Ro=N-c1u-coon' nnr-om-oo'on Typical examples of the method in accordancewith the invention of this application are as follows:

Example 1.-Preparation of a-amino isobutyric acid.

Twenty grams of fl-amino isobutanol are added to 50 cc. of watercontaining 12 g. of sodium hydroxide. 24 g. of benzaldehyde are added,to produce N-benzylidene-B-amino isobutanol. Heat is evolved and twolayers formed. To the mixture are now added 47.3 g. of potassiumpermangarlate, which oxidizes the N-benzylidene-p-amino-isobutanol toN-benzylidene-a-amino-isobus tyric acid. Upon completion of theoxidation, the

for example, be accom- .4 substituted-s-axnino alcohol" I mean suchprimary alcohols.

What is claimed is:

1. The method of producing a composition selected from the classconsisting of a-amino acids and N-substituted-a-amino acids, whichcomprises treating a lower p-amino'alkanol with an aldehyde of the classconsisting of acetaldehyde and benzaldehyde, and oxidizing the methylolgroup of the. resulting N-substituted fi-amino alkanol to a carboxylgroup by treating said last- .named alkanol with potassium permanganatein kanol with an aldehyde of the class consisting manganese dioxideproduced is removed and the filtrate is hydrolyzed with hydrochloricacid to remove the benzylidene radical and form the hydrochloride ofa-amino-isobutyric acid; and

the solution is evaporated to dryness. By treat-' ment with pyridine andalcohol, the hydrochloride of the amino acid is decomposed to liberatethe free a-amino-isobutyric acid.

Example 2.-Preparation of a-amino propionic acid.

Twenty grams of ii-amino propanol are reacted with 12 g. of acetaldehydein the presence of sodium hydroxide to produceN-ethylidene-paminopropanol. To this solution are. added 55 g. ofpotassium permanganate as in Example 1, but in this case to oxidize theN-ethylidenee-amino' propanol to N-ethyiidene-a-amino propicnic acid.Upon completion of the oxidation, the manganese dioxide produced isfiltered off,

and the filtrate is hydrolyzed with dilute hydrochloric acidabout 20 to25%t'o remove the and leave the hydrochloride of a-amino-propionic acid.The solution is then evaporated to dryness and treated with pyridine andmethyl alcohol to obtain the free a-aminopropionic acid.

Example 3.-Preparation of glycine (ct-aminoacetic acid).

Thirty-two grams of p-amino ethanol are reacted with 24 grams ofacetaldehyde, desirably in the presence of sodium hydroxide, to produceN-ethylidene-s-aminoethanol. To this are 110 grams of potassiumpermanganate as in Ex-, amples 1 and 2, but in this case to oxidize theN-ethylidene-,6-amlnoethanoi to N-ethylidene-a added I of acetaldehydeand benzaldehyde, oxidizing the methylol group of the resultingN-substituted-B- amino alkanol to a carboxyl group by treating saidlast-named alkanol with potassium permanganate in an alkaline medium,and hydrolyzing the resulting N-substituted-a-amino acid to form ana-amino acid. 0

4. The method of producing an a-amino acid, which comprises treatingwith potassium permanganate in an alkaline medium anN-substitutedp-amino alkanol in which the N-substituent is a member ofthe class consisting-of ethylidene and benzylidene, and hydrolyzing theresulting N-substituted-a-amino acid to form an a-amino acid.

5. The process of producing a composition selected from the classconsisting of a-amino isobutyric acid and N-benzylidene-a-aminoisobutyric acid, which consists in reacting fi-amino isobutanol withbenzaldehyde, and reacting the resulting N-benzylidene-fl-aminoisobutanol with potassium permanganate in an alkaline medium.

6. The process of producing a composition selected from the classconsisting of a-amino isobutyric acidand N-benzylidene-a-aminoisobutyric acid, which consists in oxidizing N-benzylidene-c-aminoisobutanol by treating it with potassium permanganate in an alkalinemedium.

7. The process of producing a-amino isobutyric acid, which consists inreacting c-amino-isobutanol with benzaldehyde, reacting the resultingN-benzylidene-B-amino isobutanoi with potassium permanganate in analkaline medium, and

aminoacetic acid. Upon completion of the oxidation, the manganesedioxide produced is filtered oil, and the filtrate is hydrolyzed with 20percent hydrochloric acid to remove the ethylidene group, and leave thehydrochloride of a-amino-acetic acid. The solution is then evaporated todryness and treated with pyridine and methyl alcohol to obtain the freea-amino acetic acid,

As the foregoing formulas and examples show, the fl-amino alcohols andthe N-substituted-B- amino alcohols used are always primary alcohols;and so by the terms p-amino alcohol" and "N- removing the benzylideneradical from the resultant N-benzylidene-a-amino isobutyric acid byhydrolysis.

8. The method of producing m-arnino isobutyric acid, which consists intreating N-benzylidene-pamino isobutanol with potassium permanganate inan alkaline medium, and removing the benzylidene group from theresultant N-benzylidenea-amino isobutyric acid by hydrolysis.

9. The process of producing a composition selected from the classconsisting of a-amino propionic acid and N-ethylidene-a-amino propionicacid, which consists in reacting p-amino propanol with acetaldehyde, andreacting the resulting N-ethylidene-p-amino propanol with potassiumpermanganate in an alkaline medium.

10. The process of producing a composition selected from the classconsisting of a-amino promanaganate in an alkaline medium, and removingthe ethylidene radical from the resultant N- ethylidene-e-aminopropionic acid by hydrolysis.

12. The method of producing a-amino propionic acid, which consists intreating N-ethylidene-pamino propanol with potassium permanganate in analkaline medium, and removing the ethylidene group from the resultantN-ethylidene-a-amino propionic acid by hydrolysis.

13. The processof producing a composition selected from the classconsisting of a-amino acetic acid and N -ethylidene-a-amino acetic acid,which consists in reacting B-amino ethanol with acetaldehyde, andreacting the resulting N-ethylidenein an alkaline medium.

14. The process of producing a composition selected from the classconsisting of a-amino acetic acid and N-ethylidene-a-amino acetic acid,which consists in oxidizing N-ethylidene-{l-amino ethanol by treating itwith potassium permanganate in an alkaline medium.

15. The process of producing a-amino acetic acid, which consists inreacting p-amino-ethanol with acetaldehyde, reacting theresultingN-ethylidene-e-amino ethanol with potassium permanganate in analkaline medium, and removingthe ethylidene radical from the resultantN-ethyli dene-a-amino acetic acid by hydrolysis.

16. The method of producing m-amino acetic acid, which consists intreating N-ethylidene-flamino ethanol with potassium permanganate in analkaline medium and removing the ethylidene group from the resultantN-ethylidene-a-amino acetic acid by hydrolysis.

JOHN H. BIILMAN.

